EP2262766B1 - Amide compounds, compositions and uses thereof - Google Patents

Amide compounds, compositions and uses thereof Download PDF

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Publication number
EP2262766B1
EP2262766B1 EP09716825.6A EP09716825A EP2262766B1 EP 2262766 B1 EP2262766 B1 EP 2262766B1 EP 09716825 A EP09716825 A EP 09716825A EP 2262766 B1 EP2262766 B1 EP 2262766B1
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EP
European Patent Office
Prior art keywords
substituted
unsubstituted
methylpyridin
mmol
benzamide
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EP09716825.6A
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German (de)
English (en)
French (fr)
Other versions
EP2262766A2 (en
Inventor
Zhi-Liang Wei
Sumithra Gowlugari
Carl Kaub
Zhan Wang
Yeyu Cao
John Kincaid
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Evotec OAI AG
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Evotec OAI AG
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • pyridylphenyl amide compounds and pharmaceutical compositions comprising such compounds.
  • compounds for use in methods for preventing and/or treating conditions in mammals such as (but not limited to) arthritis, Parkinson's disease, Alzheimer's disease, asthma, myocardial infarction, pain syndromes (acute and chronic or neuropathic), neurodegenerative disorders, schizophrenia, cognitive disorders, anxiety, depression, inflammatory bowel disease and autoimmune disorders, and promoting neuroprotection, using the compounds and pharmaceutical compositions provided herein.
  • US 2007049609 , US 2007049610 , US 2007049758 , and US 2007049534 describe certain diaminopyrimidines as P2X 3 and P2X 2/3 modulators.
  • WO 06/119504 describes fused heterocyclic compounds as P2X 3 and P2X 2/3 modulators for use in the treatment of various diseases.
  • WO04/56774 describes certain substituted biphenyl-4-carboxylic acid arylamide analogues having possible application as receptor modulators.
  • WO 08/119773 describes amide derivatives as inhibitors of aspartyl proteases and their use in the treatment of Alzheimer's disease.
  • WO 05/065195 describes certain phenylamides and pyridylamides as ⁇ -secretase inhibitors.
  • WO 02/070469 describes certain substituted sulfonylalkylcarboxamides as selective pde3b inhibitors
  • WO 04/039753 describes certain benzoic acids and related compounds as EP1 receptor antagonists for the treatment of prostaglandin mediated diseases.
  • WO03/104230 describes certain bicyclic pyrimidine derivatives
  • US Published Application Serial No. 20030092908 and WO02/087513 describe fused heterocyclic PDE7 inhibitors.
  • U.S. Patent Nos. 3,424,760 and 3,424,761 both describe a series of 3-ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacologic activities. These patents specifically disclose the compounds 1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and 1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.
  • International Patent Applications, Publication Numbers WO 01/62737 and WO 00/69849 disclose a series of pyrazole derivatives which are stated to be useful in the treatment of disorders and diseases associated with the NPY receptor subtype Y5, such as obesity.
  • WO 01/62737 specifically discloses the compound 5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.
  • WO 00/69849 specifically discloses the compounds 5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)
  • German Patent Application Number 2502588 describes a series of piperazine derivatives. This application specifically discloses the compound N-[3-[2-(diethylamino)ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolinyl]-4-phenyl-1-piperazinecarboxamide.
  • Pyridylphenyl amide compounds, and pharmaceutical compositions thereof, having potency and selectivity in the prevention and treatment of conditions that have been associated with neurological and inflammatory disorders and dysfunctions are provided herein.
  • compounds, pharmaceutical compositions and methods provided are useful to treat, prevent or ameliorate a range of conditions in mammals such as, but not limited to, pain of various genesis or etiology, for example acute, chronic, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache).
  • compounds, pharmaceutical compositions and methods provided are useful for the treatment of inflammatory pain and associated hyperalgesia and allodynia.
  • compounds, pharmaceutical compositions and methods provided are useful for the treatment of neuropathic pain and associated hyperalgesis and allodynia ( e . g .
  • compounds, pharmaceutical compositions and methods provided are useful as anti-inflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, asthma, myocardial infarction, neurodegenerative disorders, inflammatory bowel disease and autoimmune disorders, renal disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, and lipid disorders.
  • each A, B, and W is CH.
  • L is selected from -CH 2 -, -CHMe-, -CMe 2 -, -CH(CH 2 OH)-, and -CH(CH 2 CH 2 OH)-.
  • L is selected from -CH 2 -, and -CHMe-.
  • the compound is according to formula 2c, 2d, 2e, 2f, 2h, or 2i: wherein
  • compositions comprising a pyridylphenyl amide provided herein, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • compounds for use in methods are provided for preventing, treating or ameliorating a condition from among those listed herein, and particularly, such condition as may be associated with, e.g ., arthritis, asthma, myocardial infarction, lipid disorders, cognitive disorders, anxiety, schizophrenia, depression, memory dysfunctions such as Alzheimers disease, inflammatory bowel disease and autoimmune disorders, which method comprises administering to a mammal in need thereof an amount of one or more of the compounds as provided herein, or pharmaceutical composition thereof, effective to prevent, treat or ameliorate the condition.
  • compounds for use in methods for preventing, treating or ameliorating a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves in a mammal.
  • the compounds provided herein have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and ur
  • a neurodegenerative disease or disorder can, for example, be Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and
  • the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments, or as medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified.
  • methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below.
  • provided are methods of making enantiomerically pure compounds according to formula 1 by asymmetric synthesis.
  • provided are methods of making enantiomerically pure compounds according to formula 1 by chiral resolution.
  • analogue means one analogue or more than one analogue.
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are-C(O)H, -C(O)-C 1 -C 8 alkyl, -C(O)-(CH 2 ) t (C 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyl' or 'Substituted Alkanoyl' refers to a radical -C(O)R 21 , wherein R 21 is independently
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein.
  • Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • Particular exemplary 'acylamino' groups are-NR 24 C(O)-C 1 -C 8 alkyl, -NR 24 C(O)-(CH 2 ) t (C 6 -C 10 aryl), -NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -NR 24 C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or C 1 -C 8 alkyl.
  • Substituted Acylamino' refers to a radical -NR 25 C(O)R 26 , wherein:
  • 'Acyloxy' refers to a radical -OC(O)R 27 , where R 27 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are-C(O)H, -C(O)-C 1 -C 8 alkyl, -C(O)-(CH 2 ) t (C 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • Substituted Acyloxy' refers to a radical -OC(O)R 28 , wherein R 28 is independently
  • alkoxy' refers to the group -OR 29 where R 29 is C 1 -C 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • Exemplary 'substituted alkoxy' groups are -O-(CH 2 ) t (C 6 -C 10 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, and OCH 2 CH 2 NMe 2 .
  • 'Alkoxycarbonyl' refers to a radical -C(O)-OR 30 where R 30 represents an C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein.
  • alkoxycarbonyl groups are C(O)O-C 1 -C 8 alkyl, -C(O)O-(CH 2 ) t (C 6 -C 10 aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -C(O)O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • Alkoxycarbonyl' refers to a radical -C(O)-OR 31 where R 31 represents:
  • 'Aryloxycarbonyl' refers to a radical -C(O)-OR 32 where R 32 represents an C 6 -C 10 aryl, as defined herein.
  • exemplary "aryloxycarbonyl” groups is -C(O)O-(C 6 -C 10 aryl).
  • Aryloxycarbonyl' refers to a radical -C(O)-OR 33 where R 33 represents
  • Heteroaryloxycarbonyl' refers to a radical -C(O)-OR 34 where R 34 represents a 5-10 membered heteroaryl, as defined herein.
  • An exemplary "aryloxycarbonyl” group is-C(O)O-(5-10 membered heteroaryl).
  • Heteroaryloxycarbonyl refers to a radical -C(O)-OR 35 where R 35 represents:
  • 'Alkoxycarbonylamino' refers to the group -NR 36 C(O)OR 37 , where R 36 is hydrogen, C 1 -Cg alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein, and R 37 is C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms. Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
  • 'Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or -OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR"-alkoxycarbonyl or -NH-C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR" 2 ), aminocarbonylamino (-NR"-C(O)-NR" 2 ), aminocarbonyloxy (-O-C(O)-NR" 2 ), aminosulfony
  • 'substituted alkyl' refers to a C 1 -C 8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR"'SO 2 R", -SO 2 NR"R"', -C(O)R", -C(O)OR", -OC(O)R", -NR"'C(O)R", - C(O)NR"R"', -NR"R"', or -(CR”'R”") m OR"'; wherein each R" is independently selected from H, C 1 -C 8 alkyl, -(CH 2 ) t (C 6 -C 10 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C 10 cycloalkyl), and -(CH 2 ) t (4-10 membered heterocycloalky
  • 'Alkylene' refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers ( e . g .,-CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • 'Substituted alkylene' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2
  • alkenyl' refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • 'Substituted alkenyl' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-
  • Alkenylene' refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 11 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • Alkynyl' refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 11 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation.
  • alkynyl groups include acetylenic, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • 'Substituted alkynyl' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alky
  • 'Amino' refers to the radical -NH 2 .
  • 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R 38 ) 2 where each R 38 is independently selected from:
  • 'Alkylamino' refers to the group -NHR 40 , wherein R 40 is C 1 -C 8 alkyl.
  • Substituted Alkylamino' refers to the group -NHR 41 , wherein R 41 is C 1 -C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Alkylarylamino' refers to the group -NR 42 R 43 , wherein R 42 is aryl and R 43 is C 1 -C 8 alkyl.
  • Substituted Alkylarylamino' refers to the group -NR 44 R 45 , wherein R 44 is aryl and R 45 is C 1 -C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C
  • 'Arylamino' means a radical -NHR 46 where R 46 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl as defined herein.
  • Arylamino' refers to the group -NHR 47 , wherein R 47 is independently selected from C 6 -C 10 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 48 R 49 , wherein each of R 48 and R 49 are independently selected from C 1 -C 8 alkyl.
  • Dialkylamino' refers to the group -NR 50 R 51 , wherein each of R 59 and R 51 are independently selected from C 1 -C 8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy
  • 'Diarylamino' refers to the group -NR 52 R 53 , wherein each of R 52 and R 53 are independently selected from C 6 -C 10 aryl.
  • 'Aminosulfonyl' or 'Sulfonamide' refers to the radical -S(O 2 )NH 2 .
  • 'Substituted aminosulfonyl' or 'substituted sulfonamide' refers to a radical such as -S(O 2 )N(R 54 ) 2 wherein each R 54 is independently selected from:
  • Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are-S(O 2 )N(R 55 )-C 1 -C 8 alkyl, -S(O 2 )N(R 55 )-(CH 2 ) t (C 6 -C 10 aryl), -S(O 2 )N(R 55 )-(CH 2 ) t (5-10 membered heteroaryl), -S(O 2 )N(R 55 )-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S(O 2 )N(R 55 )-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R 55 independently represents H or C 1 -C 8 alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted
  • 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
  • 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.
  • Particularly aryl groups include phenyl
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, cyano, hydroxy, C 1 -C 8 alkoxy, and amino.
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or
  • R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, substituted aryl, 5-10 membered heteroaryl.
  • Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
  • 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
  • Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(O)NH 2 .
  • Carbamoyl or substituted amido' refers to the radical -C(O)N(R 62 ) 2 wherein each R 62 is independently
  • Carboxy' refers to the radical -C(O)OH.
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent.
  • 'Cyano' refers to the radical -CN.
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • heteroaryls examples include the following: wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • each W is selected from C(R 66 ) 2 , NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • heterocycloalkyl refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • thiomorpholine and its S-oxide and S,S-dioxide particularly thiomorpholine
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • heterocycloalkyl groups are shown in the following illustrative examples: wherein each W is selected from CR 67 , C(R 67 ) 2 , NR 67 , O and S; and each Y is selected from NR 67 , O and S; and R 67 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl,
  • These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carb
  • 'Hydroxy' refers to the radical -OH.
  • 'Nitro' refers to the radical -NO 2 .
  • Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • the substituents areselected from the group consisting of:
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • Substituted sulfanyl' refers to the group -SR 74 , wherein R 74 is selected from:
  • Exemplary 'substituted sulfanyl' groups are -S-(C 1 -C 8 alkyl) and -S-(C 3 -C 10 cycloalkyl), -S-(CH 2 ) t (C 6 -C 10 aryl), -S-(CH 2 ) t (5-10 membered heteroaryl), -S-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4
  • 'substituted sulfanyl' includes the groups 'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyl' or 'cycloalkylthio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or 'arylthio' and 'heteroarylsulfanyl' or 'heteroarylthio' as defined below.
  • 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR 75 where R 75 is a C 1 -C 8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
  • 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR 76 where R 76 is a C 1 -C 8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR 77 where R 77 is a C 3 -C 10 cycloalkyl or group as defined herein.
  • Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
  • 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR 78 where R 78 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR 79 where R 79 is a C 6 -C 10 aryl group as defined herein.
  • 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR 80 where R 80 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfinyl' refers to the group -S(O)R 81 , wherein R 81 is selected from:
  • Exemplary 'substituted sulfinyl' groups are -S(O)-(C 1 -C 8 alkyl) and -S(O)-(C 3 -C 10 cycloalkyl), -S(O)-(CH 2 ) t (C 6 -C 10 aryl), -S(O)-(CH 2 ) t (5-10 membered heteroaryl), -S(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4
  • substituted sulfinyl includes the groups 'alkylsulfinyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfinyl', 'arylsulfinyl' and 'heteroarylsulfinyl' as defined herein.
  • Alkylsulfinyl' refers to a radical -S(O)R 82 where R 82 is a C 1 -C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
  • Alkylsulfinyl refers to a radical -S(O)R 83 where R 83 is a C 1 -C 8 alkyl group as defined herein. substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfinyl' refers to a radical -S(O)R 84 where R 84 is a C 3 -C 10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C 3 -C 10 cycloalkyl.
  • cycloalkylsulfinyl refers to the group -S(O)R 85 where R 85 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfinyl' refers to a radical -S(O)R 86 where R 86 is a C 6 -C 10 aryl group as defined herein.
  • Heteroarylsulfinyl' refers to a radical -S(O)R 87 where R 87 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfonyl' refers to the group -S(O) 2 R 88 , wherein R 88 is selected from:
  • Exemplary 'substituted sulfonyl' groups are -S(O) 2 -(C 1 -C 8 alkyl) and -S(O) 2 -(C 3 -C 10 cycloalkyl), -S(O) 2 -(CH 2 ) t (C 6 -C 10 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl),-S(O) 2 -(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S(O) 2 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, un
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • Alkylsulfonyl' refers to a radical -S(O) 2 R 89 where R 89 is an C 1 -C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
  • Substituted Alkylsulfonyl refers to a radical -S(O) 2 R 90 where R 90 is an C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfonyl' refers to a radical -S(O) 2 R 91 where R 91 is a C 3 -C 10 cycloalkyl or group as defined herein.
  • Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
  • cycloalkylsulfonyl refers to the group -S(O) 2 R 92 where R 92 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfonyl' refers to a radical -S(O) 2 R 93 where R 93 is an C 6 -C 10 aryl group as defined herein.
  • Heteroarylsulfonyl' refers to a radical -S(O) 2 R 94 where R 94 is an 5-10 membered heteroaryl group as defined herein.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O) 2 OR 95 , wherein R 95 is selected from:
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(C 1 -C 8 alkyl) and -S(O) 2 -O-(C 3 -C 10 cycloalkyl), -S(O) 2 -O-(CH 2 ) t (C 6 -C 10 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -S(O) 2 -O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl
  • 'Thiol' refers to the group -SH.
  • 'Aminocarbonylamino' refers to the group -NR 96 C(O)NR 96 R 96 where each R 96 is independently hydrogen C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R 96 groups, when attached to the same N, are joined to form an alkylene group.
  • 'Bicycloaryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • bicycloheteroaryl refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxa
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
  • 'Cycloalkylalkyl refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
  • Heterocycloalkylalkyl refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
  • 'Cycloalkenyl' refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • cycloalkenyl refers to those groups recited in the definition of "substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-
  • Cycloalkenyl' refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • 'Ethylene' refers to substituted or unsubstituted -(C-C)-.
  • 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality.
  • Examples of 'hydrogen bond donor' groups include -OH, -NH 2 , and -NH-R 97 and wherein R 97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
  • 'Dihydroxyphosphoryl' refers to the radical -PO(OH) 2 .
  • 'Substituted dihydroxyphosphoryl' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
  • 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH 2 .
  • 'Substituted aminohydroxyphosphoryl' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
  • Heterocycloalkyl' group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • 'Solvate' encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Therapeutically effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an 'isotopic variant' of a compound can contain one or more nonradioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • nonradioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the "R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “enantiomerically pure R-compound” refers to at least about 80% by weight R-compound and at most about 20% by weight S-compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound.
  • the weights are based upon total weight of compound.
  • the term “enantiomerically pure S-compound” or “S-compound” refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R-compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound.
  • the weights are based upon total weight of compound.
  • an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • provided herein are compounds useful for preventing and/or treating a broad range of conditions, among them, arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prophylaxis of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders or conditions in mammals.
  • compositions of compounds according to formula 1 wherein A, B, W, X', L, R 1 , R 3 , R 4b , and m' are as described above; provided that
  • each A, B, and W is CH.
  • L is selected from -CH 2 -, -CHMe-, -CMe 2 -, -CH(CH 2 OH)-, and -CH(CH 2 CH 2 OH)-.
  • L is selected from -CH 2 -, and -CHMe-.
  • the compound is according to formula 2c, 2d, 2e, 2f, 2h, 2i, 2j, or 2k: wherein X', R 1 , R 3a , R 3b , R 4b , and m' are as described for formula 1; R 2a is H, Me, CH 2 OH, or CH 2 CH 2 OH; Het is substituted or unsubstituted heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, tautomer or isotopic variant thereof.
  • each R 4b is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
  • the compound is according to formula 3c, 3d, 3e, 3f, 3h, 3i, 3j, or 3k: wherein X', R 1 , R 3a , R 3b , R 4b , and m' are as described for formula 1; R 2a is H, Me, CH 2 OH, or CH 2 CH 2 OH; Het is substituted or unsubstituted heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, tautomer or isotopic variant thereof.
  • R 3a is substituted or unsubstituted alkyl.
  • R 3a is Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF 3 , CH 2 CF 3 , or benzyl.
  • R 3a is substituted methyl.
  • R 3a is methoxymethyl, methoxyethyl, dimethylaminomethyl, or dimethylaminoethyl.
  • R 3a is heteroarylmethyl, or heterocycloalkylmethyl.
  • R 3a is heteroarylethyl, or heterocycloalkylethyl.
  • R 3a is pyridylmethyl.
  • R 3a is piperidinylmethyl, piperazinylmethyl, pyrrolidinylmethyl, or morpholinylmethyl.
  • R 3a is pyridylethyl, piperidinylethyl, piperazinylethyl, pyrrolidinylethyl, or morpholinylethyl.
  • the compound is of formula 3b, and R 3a is piperidinylmethyl, piperazinylmethyl, pyrrolidinylmethyl, or morpholinylmethyl.
  • R 3a is cyclopropyl, cyclopenyl, cyclopropylmethyl, or cyclopentylmethyl.
  • R 3a is substituted or unsubstituted heteroaryl.
  • R 3a is substituted or unsubstituted pyridyl, pyrazinyl or pyrimidinyl.
  • R 3a is substituted or unsubstituted phenyl.
  • R 3a is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, thiadiazolyl, unsubstituted or substituted with alkyl or haloalkyl.
  • R 3a is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, and indolyl.
  • R 3a is and wherein subscript n1 is selected from 1-5 and each R 5a is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosul
  • R 3b is H or alkyl.
  • R 3b is H, Me, Et, or i-Pr.
  • Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, and azepin-1-yl, unsubstituted or substituted with one or more groups selected from alkyl, alkoxy, dialkylamino, halo, haloalkyl, hydroxy, or hydroxyalkyl.
  • Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, and azepin-1-yl, unsubstituted or substituted with one or more groups selected from Me, Et, i-Pr, OMe, NMe 2 , Cl, F, OH, or CF 3 .
  • the compound is according to formula 4, 5, 6, 7, 8, or 9: wherein
  • the subscript m' is 1, 2 or 3.
  • the compound is according to formula 10, 11, 12, 13, 14, or 15: wherein
  • R 2a is H, Me, CH 2 OH, or CH 2 CH 2 OH.
  • R 2b is H.
  • n3 is 1 or 2.
  • R 5c is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
  • R 5c is from H, Cl, F, Me, OMe, or CF 3 .
  • R 4b is H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl or halo.
  • R 4b is H, Me, CF 3 , Cl, Br, or F.
  • R 1 is substituted or unsubstituted aryl or heteroaryl.
  • R 1 is substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is substituted or unsubstituted pyridyl, pyrazinyl, thiazolyl, or pyrimidinyl.
  • R 1 is substituted or unsubstituted pyridyl.
  • R 1 is substituted or unsubstituted pyrimidyl.
  • R 1 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, and indolyl.
  • R 1 is and wherein subscript n2 is selected from 1-5 and each R 5b is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted
  • subscript n2 is 1, 2 or 3.
  • subscript n2 is 1 or 2.
  • R 1 is and wherein R 5b is as described above.
  • each R 5b is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
  • each R 5b is independently selected from H, Cl, F, Me, OMe, or CF 3 .
  • each R 5b is Me.
  • each R 5b is OMe.
  • each R 5b is CF 3 .
  • R 1 is selected from hydroxy C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, or 4-7 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • R 1 is selected from hydroxymethyl, 1-hydroxyethyl, and 2-hydroxyethyl.
  • R 1 is selected from piperidin-1-ylmethyl, piperazin-1-ylmethyl, and morpholin-1-ylmethyl.
  • R 2a is hydrogen
  • R 2a is methyl, hydroxymethyl or hydroxyethyl.
  • R 2a is methyl
  • the compound is according to formula 19, 20, or 21: wherein
  • R 5b is Me.
  • R 5b is CF 3 .
  • R 5b is OMe.
  • Cy is morpholin-1-yl.
  • R 2a is H.
  • R 2a is Me.
  • R 2a is CH 2 OH.
  • R 4b is Me.
  • R 3a is Me, Et, i-Pr, n-Pr, i-Bu, t-Bu, CF 3 , CH 2 CF 3 , or benzyl.
  • R 3a is methoxymethyl, methoxyethyl, dimethylaminomethyl, or dimethylaminoethyl.
  • R 3a is piperidinylmethyl, piperazinylmethyl, pyrrolidinylmethyl, or morpholinylmethyl.
  • R 3a is pyridylmethyl, pyridylethyl, piperidinylethyl, piperazinylethyl, pyrrolidinylethyl, or morpholinylethyl.
  • R 3a is cyclopropyl, cyclopenyl, cyclopropylmethyl, or cyclopentylmethyl.
  • R 3a is substituted or unsubstituted phenyl, pyridyl, pyrazinyl or pyrimidinyl.
  • R 3a is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, thiadiazolyl, unsubstituted or substituted with alkyl or haloalkyl.
  • R 3a is quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, and indolyl.
  • R 3b is H, Me, Et, or i-Pr.
  • R 3b is H.
  • Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, and azepin-1-yl, unsubstituted or substituted with one or more groups selected from Me, Et, i-Pr, OMe, NMe 2 , Cl, F, OH, or CF 3 .
  • the compound is selected from the compounds exemplified in Table 1.
  • the compound is 3-(4-Hydroxy-pyrrolidin-3-yloxy)-5-(5-methyl-pyridin-2-yl)-N-[(R)-1-(2-methyl-pyrimidin-5-yl)-ethyl]-benzamide; or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer or isotopic variant thereof.
  • the compound is selected from
  • Certain compounds provided herein have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 ).
  • compositions When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds provided herein are administered in a therapeutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • a compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.
  • a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture is stirred until it congeals.
  • the present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans and non-human mammals.
  • the present invention includes within its scope, and extends to, the recited compounds for use in methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.
  • a compound for use in a method of treatment aspect comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
  • a compound for use in a method of treatment aspect is a compound for use in a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves.
  • the present compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache).
  • acute, inflammatory pain such as pain associated with osteoarthritis and rheumatoid arthritis
  • various neuropathic pain syndromes such
  • neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteo
  • the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds provided herein When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives. Adminsitration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See , e.g., Synthetic Schemes 1-11 below. It will be appreciated that where typical or preferred process conditions (i.e. , reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Projecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 , and references cited therein.
  • the compounds provided herein may be prepared by the reaction of a carboxylic acid with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative substituted biarylamides that have been listed herein.
  • the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • the enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer. See , e.g., " Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981 ); S.H. Wilen, A. Collet, and J.
  • an enantiomerically pure compound of formula 1 may be obtained by reaction of the racemate with a suitable optically active acid or base.
  • suitable acids or bases include those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York ; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514 ; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512 ; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation , the contents of which are hereby incorporated by reference in their entireties.
  • Enantiomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used.
  • the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
  • the diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid.
  • the other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.
  • enantiomerically pure compound can be separated from racemic compound by chiral chromatography.
  • Various chiral columns and eluents for use in the separation of the enantiomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
  • Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • each of X and X 1 is independently selected from F, Cl, Br, I, and OTf;
  • X" is F, Cl, Br, I, Ts, or OH; or R is selected from C 1 -C 6 alkyl, and benzyl; and
  • A, B, W, X', L, R 1 , R 3a , R 3b , R 4b , L and m' are as described herein.
  • a microwave vial was charged with 6-cyanobenzo[b]thiophene-2-carboxylic acid (1.90 g, 9.35 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol) and N,N- dimethylacetamide (15 mL) and the reaction was subjected to microwave irradiation at 190 °C for 1 hour. After cooling, the reaction mixture was poured into 1N aq. HCl and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to get the product as light brown solid.
  • a hydrogenation par vessel was charged with 1,1-dioxo-1H-benzo[b]thiophene-6-carbonitrile (0.30 g, 1.57 mmol), ethanol (25 mL) and palladium hydroxide (66 mg). The vessel was put on a shaker under hydrogen at 40 Psi for 5 h. The reaction mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated to get the product as a white solid.
  • Triethylamine (110 mL, 0.82 mol) was slowly added at -78 °C and then the mixture was slowly warmed to room temperature and stirred for another 1 hr. The mixture was treated with water and the aqueous phase was extracted with CH 2 Cl 2 (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated. The residue was purified by silica gel column to afford the title compound.
  • Lithium tetrahydroaluminate (0.50 g, 13.2 mmol) was slowly added in small portions to an ice-cooled solution of ethyl imidazo[1,2-a]pyridine-7-carboxylate (2.20 g, 11.6 mmol) in THF (150 mL). The mixture was slowly warmed to rt and stirred at rt overnight. The solution was cooled to 0 °C and quenched carefully with 1N aq. HCl (10 mL). Solid K 2 CO 3 and anhydrous Na 2 SO 4 were added and the mixture was stirred at rt for 30 min. The mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated to yield the crude product as a solid (1.68 g, 80% purity) which was used for the next step without further purification.
  • Aqueous sodium hydroxide (6 N) was then added dropwise till the pH of the reaction mixture reaches 10 and the reaction was stirred overnight.
  • the reaction was then made acidic (pH 2) by addition of 2N HCl.
  • the solids formed were filtered and dried to get 4-methyl-3-sulfinobenzoic acid as a white solid.
  • This compound (55 g, 0.275 mol) was charged into a round bottom flask containing potassium carbonate (75.8 g, 0.55 mol) and N,N- dimethylformamide (450 mL).
  • Methyl iodide (68.1 mL, 1.10 mol) was added slowly and the reaction was stirred for 4 hours.
  • the reaction mixture was then diluted with water and extracted with EtOAc. The solvents were removed under reduced pressure to get the title compound as a white solid.
  • Aqueous sodium hydroxide (6 N) was then added drop wise till the pH of the reaction mixture reaches 10 and the reaction was stirred over night.
  • the reaction was then made acidic (pH 2) by addition of 2N HCl.
  • the solids formed were filtered and dried to get the title compound as a white solid.
  • the title compound was isolated as a white foam from the preparation of compound 15 as the crude 5-(ethoxycarbonyl)-4'-methylbiphenyl-3-carboxylic acid contained some 4'-methylbiphenyl-3,5-dicarboxylic acid.
  • a Parr pressure reactor was charged with dimethyl 5-bromoisophthalate (1.3 g, 4.8 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.0 g, 5.9 mmol), toluene (25 mL), ethanol (5 mL), cesium carbonate (1.7 g, 5.2 mmol), and water (2.5 mL).
  • the mixture was degassed and purged with nitrogen several times before tetrakis(triphenylphosphine)-palladium(0) (280 mg, 0.24 mmol) was added. The tube was sealed and the mixture was heated at 90°C overnight.
  • the reaction mixture was stirred for 16 hours at 25 °C.
  • the reaction mixture was purified by preparative HPLC to yield Boc protected product as a white solid, which was dissolved in methylene chloride (3.0 mL) and trifluoroacetic acid (0.20 mL, 2.6 mmol) was added.
  • the reaction mixture was stirred at rt overnight.
  • the volatiles were removed in vacuo and the residue was purified by preparative HPLC (100 x 21.2 mm C18 column, 20-60% MeCN/water[10 mM Et 2 NH]) to afford the product as a white foam.
  • K 2 PO 4 solution 2.0 M aqueous K 3 PO 4 solution was degassed and purged with argon.
  • Boronate solution N-((6-methylpyridin-3-yl)methyl)-5-(pyrrolidine-1-carbonyl)-4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-3-carboxamide (100 mg, 0.19 mmol) was dissolved in DMF (0.8 mL). The solution was degassed and purged with argon.
  • Catalyst solution [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (10 mg, 0.012 mmol) was well dissolved in degassed N,N -dimethylformamide (5.0 mL). The solution was degassed and purged with argon. Reaction : Under argon at room temperature, a small reaction vial was charged with 1 mL of the orange-red catalyst solution (i.e. 2 mg of the catalyst was used) and iodomethane-d3 (55 mg, 0.38 mmol).
  • a microwave vial was charged with methyl 3-bromo-5-(cyclopentylsulfonyl)benzoate (0.50 g, 1.44 mmol), p-tolylboronic acid (0.44 g, 3.25 mmol), toluene (7 mL), and a solution of cesium carbonate (1.06 g, 3.26 mmol) in water (0.3 mL).
  • the vial was degassed and purged with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added.
  • the reaction mixture was subjected to microwave irradiation at 100°C for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash column (0-25% EtOAc/hexane) to yield the title compound as a colorless oil.
  • Phenylmagnesium bromide (850 mg, 4.7 mmol) was added to a solution of ethyl 5-formyl-4'-methylbiphenyl-3-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (8 mL) at 0 °C.
  • the reaction mixture was stirred at room temperature for 3 h, and then water (10 mL) was added.
  • the mixture was extracted with EtOAc (20 mL x 2).
  • the combined organic layers were dried over anhydrous MgSO 4 and concentrated. The residue was purified by silica gel column chromatography to afford the title compound.

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CN104016907A (zh) 2014-09-03
JP5539235B2 (ja) 2014-07-02
US20110065681A1 (en) 2011-03-17
CN104058999A (zh) 2014-09-24
ES2557281T3 (es) 2016-01-25
HK1149007A1 (en) 2011-09-23
JP2014065737A (ja) 2014-04-17
CA2715835A1 (en) 2009-09-11
JP5916700B2 (ja) 2016-05-11
WO2009110985A3 (en) 2010-02-25
US8946439B2 (en) 2015-02-03
CN101981003B (zh) 2014-07-02
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US20150266822A1 (en) 2015-09-24

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